Growth cones must remodel their actin cytoskeleton in response to guidance cues. How this transduction of signaling to actin dynamics occurs is largely unknown. The Ena/VASP proteins are known actin regulators implicated in axon guidance. In particular, they are targets of cyclic-nucleotide dependent kinases that are known to modify specific axonal responses to guidance cues. This proposal addresses the role of Mena, the most highly expressed family member in the nervous system, in growth cone guidance. Specific Aims: 1) To determine the role of Mena in axon guidance in response to Netrin and Slit gradients and to investigate how this role is modulated by PKA/PKG. 2) To determine which proteins associate with the phosphorylated form of Mena in neurons. These studies will identify which guidance cues require Mena protein for their function and will clarify how phosphorylation of Mena affects the response of growth cones to these cues. This information will provide a better understanding of all Ena/VASP proteins and the mechanisms that regulate axon guidance. [unreadable] [unreadable]